Traumatic optic neuropathy (TON) occurs in 0.5-5% of patients presenting with close head trauma and is often devastating cause of permanent visual loss. Damage to the optic nerve (ON) causes immediate shearing of and induces a vicious cycle of swelling and ischemia lead to RGCs and axon injury. In the majority of cases, the first critical event is RGC axonal damage, possibly mediated by glial dysfunction, following the apoptotic cell signaling, retrograde axonal degeneration and Wallerian degeneration. After ON transection, RGCs begin dying by apoptosis by first 3-7 days and the remainder (50-90%) have disappeared from the retina taking weeks to sometimes months. Axonal injury also induces a burst of superoxide within the RGC soma, following induction of downstream oxidative events and cytotoxic cytokines and results in apoptosis. Therefore, therapies that stimulate both neuronal viability and axon growth may prove beneficial after ON lesion.
The optic nerve crush model is an effective model for studying pathophysiology of RGCs death in axon injury and to evaluate the neuroprotective ability of several strategies for acute optic neuropathies. ON crush induces a retrograde degeneration of the RGCs after the injury. Prior to that, the myelin sheath of the axons degenerates, the ED-1 positive phagocytes (including macrophage and microglia) infiltrate and remove the myelin debris. Macrophage and microglia accumulation at the site of the insult contributes to glial scar formation in the ON, which is an obstacle for regeneration. These observations have implicated important roles of inflammatory processes in the ON crush injury. Inhibition of glial activation by both nitric oxide inhibitors and anti-inflammatory cytokines has been used to rescue RGC from apoptosis after axon injury.
In recent years, numerous marine invertebrates based compounds have been reported to show extensive anti-inflammatory activities, stimulation of neurogenesis, and modulation of receptors or voltage gated channels in central nervous system (CNS). Previous studies of bioactive marine natural products have led to isolation of several compounds with neuroprotective and anti-inflammatory activities from soft corals. Austrasulfone, a bioactive substance isolated from the Formosan soft coral Cladiella australis, exhibits potent neuroprotective effects. Dihydroaustrasulfone alcohol, the synthetic precursor of austrasulfone, not only exhibits anti-inflammatory activity in vitro, but also shows potent therapeutic potential in the treatment of inflammatory-related diseases.
However, the precursor has high polarity that reduces the ability of the precursor to pass through cell membrane. In light of this, the polar hydroxyl group (eOH) of hydroxylated sulfone was replaced with benzene ring in a straightforward synthesis to yield the compound, 4-(Phenylsulfanyl)butane-2-one (4-PSB-2) in order to easily pass through the cell membrane.